Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(N[C:5]1[S:6][CH:7]=[CH:8][C:9]=1[C:10](=[O:18])[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=1[F:17])(=O)C.[H-].[Na+].[CH3:21]I.O.[CH3:24][N:25](C)[CH:26]=[O:27]>>[CH3:24][N:25]([C:26](=[O:27])[CH3:21])[SH:6]1[CH:7]=[CH:8][C:9]([C:10](=[O:18])[C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=2[F:17])=[CH:5]1
Reactant: CC(=O)Nc1sccc1C(=O)c1ccccc1F
Reactant: CI
Reactant: CN(C)C=O
Agent: [H-]
Agent: [Na+]
Solvent: O
Product: CC(=O)N(C)[SH]1C=CC(C(=O)c2ccccc2F)=C1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a solution of 1.0 g of 2-acetylamino-3-(o-fluorobenzoyl)thiophene in 10 ml of dimethylformamide is added 0.220 g of 63 % sodium hydride. The mixture is stirred at room temperature for 30 minutes. Then 1.0 g of methyl iodide in 1 ml of dimethylformamide is added thereto. The mixture is stirred at room temperature overnight, then poured into water, and extracted with benzene. The benzene extracts are washed with water, dried over sodium sulfate, and the solvent is removed under reduced pressure. The residual oil is chromatographed on silica gel, using chloroform as an eluent to give crystals, which are recrystallized from ether to give N-methyl-1-acetylamino-3-(o-fluorobenzoyl)thiophene as crystals having a melting point of 94° - 95°C.
Reaction SMILES: [C:1]([O:5][C:6](=[O:27])[CH2:7][C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=1[CH:14]=[CH:15][N:16]1C(=O)C2C(=CC=CC=2)C1=O)([CH3:4])([CH3:3])[CH3:2].O.NN>CCO>[C:1]([O:5][C:6](=[O:27])[CH2:7][C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=1[CH2:14][CH2:15][NH2:16])([CH3:2])([CH3:4])[CH3:3]
Reactant: CC(C)(C)OC(=O)Cc1ccccc1C=CN1C(=O)c2ccccc2C1=O
Agent: NN
Solvent: CCO
Solvent: O
Product: CC(C)(C)OC(=O)Cc1ccccc1CCN
Yield: 66.9 %

Procedure:
A solution of {2-[2-(1,3-dioxo-1,3-dihydro-isoindol-2-yl)-vinyl]-phenyl}-acetic acid tert-butyl ester (1.97 g) and hydrazine hydrate (1.97 mL) in EtOH (75 mL) was heated at reflux for 90 minutes. The solids were removed by filtration and the filtrate was concentrated in vacuo. The residue was dissolved in EtOAc (50 mL) and the solution was washed with saturated NaHCO3 followed by brine. The organic solution was dried over MgSO4, filtered, and concentrated. Purification by flash chromatography (CHCl3:MeOH 97.5:2.5 to 95:5 to 9:1) provided the title amine (853 mg). MS 236 (M+1).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[N:5][NH:6][CH:7]=1.O1[CH2:12][CH2:11][CH2:10][CH2:9]1.C(Br)(CC)C>O>[CH:10]([N:5]1[CH:4]=[C:3]([O:2][CH3:1])[CH:7]=[N:6]1)([CH2:11][CH3:12])[CH3:9]
Reactant: C1CCOC1
Reactant: COc1cn[nH]c1
Solvent: O
Solvent: CCC(C)Br
Product: CCC(C)n1cc(OC)cn1
Temperature: 70 °C
Reaction time: 18 h
Yield: 42 %

Procedure:
A mixture of 23.6 g (0.21 mol) of potassium tert.-butylate, 19.6 g (0.2 mol) of 4-methoxypyrazole (for the preparation, see Archiv der Pharmazie 300 (1967), pages 704-708), 100 ml of tetrahydrofuran and 28.7 g (0.21 mol) of sec.-butyl bromide was stirred at 70° C. for 18 hours. 300 ml of water were then added and the mixture was extracted 3 times with 100 ml of chloroform each time. The combined organic phases were dried over sodium sulphate and evaporated in vacuo. 13.2 g (42% of theory) of 1-sec.-butyl-4-methoxypyrazole were obtained from the residue, by vacuum distillation, in the form of a colorless oil with a boiling point of 60° C./0.2 mm Hg.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([NH2:21])[CH:5]=[CH:6][C:7]=1[O:8][C:9]1[C:10]2[N:17]([CH:18]([CH3:20])[CH3:19])[CH:16]=[CH:15][C:11]=2[N:12]=[CH:13][N:14]=1.[C:22]1([CH2:28][C:29]([N:31]=[C:32]=[S:33])=[O:30])[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1>C1COCC1>[F:1][C:2]1[CH:3]=[C:4]([NH:21][C:32]([NH:31][C:29](=[O:30])[CH2:28][C:22]2[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=2)=[S:33])[CH:5]=[CH:6][C:7]=1[O:8][C:9]1[C:10]2[N:17]([CH:18]([CH3:19])[CH3:20])[CH:16]=[CH:15][C:11]=2[N:12]=[CH:13][N:14]=1
Reactant: CC(C)n1ccc2ncnc(Oc3ccc(N)cc3F)c21
Reactant: O=C(Cc1ccccc1)N=C=S
Solvent: C1CCOC1
Product: CC(C)n1ccc2ncnc(Oc3ccc(NC(=S)NC(=O)Cc4ccccc4)cc3F)c21
Reaction time: 3 h
Yield: 24.7 %

Procedure:
To a suspension of 248 (10 mg, 0.035 mmol) in THF (1 mL) was added 2-phenylacetyl isothiocyanate (0.007 mL, 0.038 mmol). The reaction mixture was stirred for 3 hours, concentrated under reduced pressure and the residue was purified by flash chromatography, eluent EtOAc/hexane (1:1) and preparative HPLC (C-18 Aquasyl column, gradient: 60% to 95% MeOH in water, 45 min), to afford title compound 249 (4 mg, 26% yield) as a white solid. 1HNMR: (CD3OD) δ (ppm): 8.35(s, 1H), 8.03 (d, J=12.4 Hz, 1H), 7.96(d, J=3.13 Hz, 1H), 7.44-7.26(m, 6H), 6.69 (d, J=3.13 Hz, 1 H), 5.29 (quintuplet, J=6.65 Hz, 1H), 3.75(s, 2H), 3.60 (d, J=10.96 Hz, 3H), 1.63(d, J=6.65 Hz, 6H). MS (m/z): 464.2 (M+1).
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([CH:8]([NH:10][C:11](=[O:17])[O:12][C:13]([CH3:16])([CH3:15])[CH3:14])[CH3:9])[CH:5]=[CH:6][CH:7]=1.[Cl:18][C:19]1[CH:20]=[CH:21][C:22](F)=[C:23]([CH:26]=1)[C:24]#[N:25].C(=O)([O-])[O-].[Cs+].[Cs+]>C(#N)C.C(OCC)(=O)C>[C:13]([O:12][C:11](=[O:17])[NH:10][CH:8]([C:4]1[CH:5]=[CH:6][CH:7]=[C:2]([O:1][C:22]2[CH:21]=[CH:20][C:19]([Cl:18])=[CH:26][C:23]=2[C:24]#[N:25])[CH:3]=1)[CH3:9])([CH3:16])([CH3:15])[CH3:14]
Reactant: CC(NC(=O)OC(C)(C)C)c1cccc(O)c1
Reactant: N#Cc1cc(Cl)ccc1F
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CCOC(C)=O
Solvent: CC#N
Product: CC(NC(=O)OC(C)(C)C)c1cccc(Oc2ccc(Cl)cc2C#N)c1
Temperature: 100 °C
Yield: 97.5 %

Procedure:
tert-Butyl [1-(3-hydroxyphenyl)ethyl]carbamate (0.025 g, 0.11 mmol) was dissolved in acetonitrile (1.0 mL) with 5-chloro-2-fluorobenzonitrile (Aldrich, Cat. #548693) (0.034 g, 0.22 mmol) and cesium carbonate (0.073 g, 0.22 mmol) in a sealed tube. The reaction was heated to 100° C. for 2 h. and was complete. The reaction was taken up in ethyl acetate, filtered and concentrated under reduced pressure to give crude tert-butyl{1-[3-(4-chloro-2-cyanophenoxy)phenyl]ethyl}carbamate (0.040 g) as a clear oil. Analytical LCMS (M+H-Boc)+: m/z=272.9.
Reaction SMILES: [CH2:1]([O:8][C:9]([N:11]1[CH2:16][CH2:15][CH2:14][C@@H:13]([CH:17]2[CH2:20][CH2:19][N:18]2CC=C)[CH2:12]1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.CN1C(=O)CC(=O)N(C)C1=O>C(Cl)Cl.CO.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[CH2:1]([O:8][C:9]([N:11]1[CH2:16][CH2:15][CH2:14][C@@H:13]([CH:17]2[CH2:20][CH2:19][NH:18]2)[CH2:12]1)=[O:10])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: C=CCN1CCC1[C@@H]1CCCN(C(=O)OCc2ccccc2)C1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: CN1C(=O)CC(=O)N(C)C1=O
Solvent: ClCCl
Solvent: CO
Product: O=C(OCc1ccccc1)N1CCC[C@@H](C2CCN2)C1
Temperature: 25 °C
Reaction time: 64 h
Yield: 89 %

Procedure:
To a solution of (R)-3-(1-allylazetidin-2-yl)piperidine-1-carboxylic acid benzyl ester (163 mg, 0.518 mmol) in DCM (10 mL) was added 1,3-dimethylbarbituric acid (243 mg, 1.56 mmol) and Pd(PPh3)4 (60 mg, 0.052 mmol). The mixture was stirred at RT for 64 h, then diluted with MeOH and loaded onto an Isolute® SCX-2 cartridge. The cartridge was washed with MeOH and the product eluted with 0.5M NH3/MeOH. Further purification by column chromatography (Si-PCC, gradient 3-15% 2M NH3/MeOH in DCM) afforded the title compound (126.5 mg, 89%) as a colourless oil. LCMS (Method B): RT1.99 & 2.07 min [M+H]+ 275.
Reaction SMILES: [C:1]([NH:11][CH2:12][CH2:13][C:14]([OH:16])=O)([O:3][CH2:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1)=[O:2].ON1[C:22](=[O:23])[CH2:21]CC1=O.C1CCC([N:31]=C=NC2CCCCC2)CC1>C1COCC1>[C:1]([NH:11][CH2:12][CH2:13][C:14]([CH:22]([CH2:21][NH2:31])[OH:23])=[O:16])([O:3][CH2:4][C:5]1[CH:6]=[CH:7][CH:8]=[CH:9][CH:10]=1)=[O:2]
Reactant: O=C(O)CCNC(=O)OCc1ccccc1
Reactant: O=C1CCC(=O)N1O
Reactant: C(=NC1CCCCC1)=NC1CCCCC1
Solvent: C1CCOC1
Product: NCC(O)C(=O)CCNC(=O)OCc1ccccc1

Procedure:
To a THF solution of N-(CBZ)-β-alanine and N-hydroxysuccinimide, add DCC. The reaction is mixed overnight at room temperature. The crude reaction mixture is filtered through a sintered glass funnel into a round bottom flask to remove the DCU that is formed. The activated ester should remain in solution. After concentrating and redissolving in solvent, ethanolamine or an alcohol protected derivative can be added as a solution to the solution containing the activated ester. Triethylamine can also be added. Workup of the reaction and purification results in formation of N-carbobenzoxy-β-alanyl-ethanolamine. The free alcohol can be sulfated by a variety of methods to result in formation of N-carbobenzoxy-β-alanyl-ethanolamine sulfate.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:11]=[CH:12][CH:13]=1)[CH:6]=[CH:7][C:8]([OH:10])=O.[O:14]1[C:18]2[CH:19]=[CH:20][C:21]([CH:23]([NH2:25])[CH3:24])=[CH:22][C:17]=2[O:16][CH2:15]1.CCN=C=NCCCN(C)C.Cl.C(N(CC)CC)C>CN(C1C=CN=CC=1)C.C(Cl)Cl.O>[O:14]1[C:18]2[CH:19]=[CH:20][C:21]([CH:23]([NH:25][C:8](=[O:10])[CH:7]=[CH:6][C:5]3[CH:11]=[CH:12][CH:13]=[C:3]([O:2][CH3:1])[CH:4]=3)[CH3:24])=[CH:22][C:17]=2[O:16][CH2:15]1
Reactant: CC(N)c1ccc2c(c1)OCO2
Reactant: COc1cccc(C=CC(=O)O)c1
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: ClCCl
Solvent: O
Solvent: CCN(CC)CC
Product: COc1cccc(C=CC(=O)NC(C)c2ccc3c(c2)OCO3)c1
Temperature: 25 °C
Reaction time: 16 h
Yield: 78 %

Procedure:
A mixture of 3-methoxycinnamic acid (2 mmole), (±)-1-benzo[1,3]dioxol-5-yl-ethylamine, Preparation 2 (396 mg, 2.4 mmole), EDC hydrochloride (768 mg, 4 mmole), DMAP (244 mg, 2 mmole), and triethylamine (404 mg, 4 mmole) in CH2Cl2 (5 mL) was stirred at room temperature for 16 hours. Water was added, and the mixture was extracted with CH2Cl2 (three times). The combined organic layers were washed with brine, dried over anhydrous sodium sulfate, filtered and the filtrate was concentrated in vacuo. The crude product was subjected to purification by flash column chromatography on silica gel eluted with EtOAc/hexane (2:1) to provide the racemic titled compound (510 mg, 78%).
Reaction SMILES: [Li+].[CH3:2][Si]([N-][Si](C)(C)C)(C)C.[N:11]1([C:22]([O:24][C:25]([CH3:28])([CH3:27])[CH3:26])=[O:23])[CH2:16][CH2:15][CH:14]([C:17]([O:19][CH2:20][CH3:21])=[O:18])[CH2:13][CH2:12]1.CN([CH2:32][CH2:33]N(C)C)C>C1COCC1.[CH2-]C=C.[CH2-]C=C.Cl[Pd+].Cl[Pd+]>[CH:33]1([C:14]2([C:17]([O:19][CH2:20][CH3:21])=[O:18])[CH2:13][CH2:12][N:11]([C:22]([O:24][C:25]([CH3:27])([CH3:26])[CH3:28])=[O:23])[CH2:16][CH2:15]2)[CH2:32][CH2:2]1
Reactant: C[Si](C)(C)[N-][Si](C)(C)C
Reactant: CCOC(=O)C1CCN(C(=O)OC(C)(C)C)CC1
Reactant: CN(C)CCN(C)C
Agent: Cl[Pd+]
Agent: C=C[CH2-]
Agent: [Li+]
Solvent: C1CCOC1
Product: CCOC(=O)C1(C2CC2)CCN(C(=O)OC(C)(C)C)CC1
Temperature: 0 °C
Reaction time: 2.5 h
Yield: 28 %

Procedure:
LHMDS (1M THF solution; 2.4 mL, 2.4 mmol) was added to a −78° C. solution of 1-tert-butyl 4-ethyl piperidine-1,4-dicarboxylate (514 mg, 2 mmol) in anhydrous THF (5 mL) and the reaction was allowed to warm to 0° C. over the course of 30 mins, whilst under an inert atmosphere. This solution was added drop-wise to a solution of allylpalladium chloride dimer (365 mg, 1 mmol), TMEDA (302 uL, 2 mmol) in anhyrdous THF (2.5 mL) in an oven dried flask under an inert atmosphere at −60° C. A balloon of carbon monoxide was attached and the reaction stirred for 2.5 h at 0° C. Saturated ammonium chloride solution (10 mL) was added, the reaction mixture extracted with Et2O (20 mL) and the organic phase washed with sat. brine (20 mL), dried (MgSO4) and concentrated in vacuo. The desired product was isolated as an oil by normal phase chromatography (Grace 12 g, 25-75% hexane:EtOAc, gradient elution; visualised with permangenate stain) (164 mg, 28% yield). 1H NMR (CDCl3) δ 4.16 (q, J=7.1 Hz, 2H), 4.08-3.84 (m, 2H), 2.72 (s, 2H), 1.99 (dd, J=13.5, 2.0 Hz, 2H), 1.43 (s, 9H), 1.33-1.16 (m, 5H), 0.91 (tt, J=8.1, 5.8 Hz, 1H), 0.41-0.26 (m, 4H).
Reaction SMILES: [Cl:1][C:2]1[C:7]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)=[N:6][N:5]=[C:4]2[N:14]([CH2:23]CO)[N:15]=[C:16]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)[C:3]=12.[CH2:26]([OH:29])[C:27]#[CH:28].C(N(CC)CC)C.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>O1CCOCC1.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[Cl:1][C:2]1[C:7]([C:8]2[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=2)=[N:6][N:5]=[C:4]2[N:14]([CH3:23])[N:15]=[C:16]([C:17]3[CH:22]=[C:21]([C:28]#[C:27][CH2:26][OH:29])[CH:20]=[CH:19][CH:18]=3)[C:3]=12
Reactant: OCCn1nc(-c2ccccc2)c2c(Cl)c(-c3ccccc3)nnc21
Reactant: C#CCO
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CCN(CC)CC
Solvent: C1COCCO1
Product: Cn1nc(-c2cccc(C#CCO)c2)c2c(Cl)c(-c3ccccc3)nnc21
Temperature: 100 °C
Yield: 38.5 %

Procedure:
A mixture of 4-chloro-3-(3-iodophenyl)-1-methyl-5-phenyl-1H-pyrazolo[3,4-c]pyridazine (Compound 7, Example 32) (80 mg, 0.18 mmol), propargyl alcohol (41 mg, 0.74 mmol), triethylamine (87 μl, 0.63 mmol), Cut (3.5 mg, 0.018 mmol), triphenylphosphine (5 mg, 0.018 mmol) and Pd(PPh3)4 (20 mg, 0.018 mmol) in 1,4-dioxane (1.5 mL) was heated at 100° C. for 4 h in a sealed tube. The reaction mixture was partitioned between CH2Cl2 and water. The organic phase was separated and dried using a phase separating cartridge then concentrated in vacuo. The crude residue was purified by column chromatography (silica gel, 20-30% ethyl acetate/isohexane), yielding Compound 30 as a solid (26 mg).
Reaction SMILES: Cl[C:2]1[C:3]([N:8]2[CH2:13][CH2:12][O:11][CH2:10][CH2:9]2)=[N:4][CH:5]=[CH:6][N:7]=1.[OH-:14].[Na+].O>CS(C)=O>[O:11]1[CH2:12][CH2:13][N:8]([C:3]2[C:2](=[O:14])[NH:7][CH:6]=[CH:5][N:4]=2)[CH2:9][CH2:10]1
Reactant: [OH-]
Reactant: Clc1nccnc1N1CCOCC1
Agent: [Na+]
Solvent: O
Solvent: CS(C)=O
Product: O=c1[nH]ccnc1N1CCOCC1
Temperature: 80 °C
Reaction time: 2 h
Yield: 74.2 %

Procedure:
A mixture of 4-(3-chloropyrazin-2-yl)morpholine (894 mg, 6 mmol) and aq NaOH (13 mL, 52 mmol) in DMSO (18 mL) was stirred at 80° C. for 2 h. The reaction mixture was poured into water (30 mL) and extracted with ethyl acetate (3×20 mL). The combined organic layers were washed with brine, dried over Na2SO4, filtered and concentrated under reduced pressure to give 3-morpholinopyrazin-2(1H)-one as a light yellow solid (807 mg, 92.9%). 1H NMR (300 MHz, CDCl3) δ 11.80 (br s, 1H), 7.05 (d, J=4.2 Hz, 1H), 6.73 (d, J=4.2 Hz, 1H), 3.84 (s, 8H). LCMS (ESI) m/z 182 (M+H)+.
Reaction SMILES: O=[C:2]1[CH2:7][CH2:6][N:5]([C:8]([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:9])[CH2:4][CH2:3]1.Br.[Br:16][C:17]1[CH:18]=[C:19]([CH:22]=[CH:23][CH:24]=1)[CH2:20][NH2:21].C(O)(=O)C.[BH3-]C#N.[Na+]>CO.O>[Br:16][C:17]1[CH:18]=[C:19]([CH2:20][NH:21][CH:2]2[CH2:7][CH2:6][N:5]([C:8]([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:9])[CH2:4][CH2:3]2)[CH:22]=[CH:23][CH:24]=1
Reactant: CC(C)(C)OC(=O)N1CCC(=O)CC1
Reactant: NCc1cccc(Br)c1
Agent: Br
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CO
Solvent: CC(=O)O
Solvent: O
Product: CC(C)(C)OC(=O)N1CCC(NCc2cccc(Br)c2)CC1
Temperature: 25 °C
Reaction time: 24 h

Procedure:
To a solution of commercially available tert-butyl 4-oxo-1-piperidine carboxylate (400 mg, 2 mmol) in methanol (1 ml) and 3-bromobenzylamine hydrobromide (222 mg, 1 mmol) in methanol (1 ml) was added acetic acid in methanol (1 M, 1.34 ml) followed by NaCNBH3 in methanol (0.3 M, 4.4 ml). The resulting solution was stirred at room temperature. After 24 h, water (2 ml) was added, and the mixture was stirred for 1 h, before it was concentrated. The resulting oil was redissolved in diethyl ether (20 ml), extracted with HCl (0.1 N, 1×15 ml). The aqueous layer was washed with diethyl ether (10 ml) and treated with 0.2 N NaOH until basic (pH>8), before extracted with dichloromethane (20 ml). The organic layer was dried (Na2SO4), filtered, and concentrated to give tert-butyl 4-((3-bromophenyl)methyl)amino-piperidine carboxylate. Yield: 142 mg. To a solution of tert-butyl 4-((3-bromophenyl)methyl)amino-piperidine carboxylate (50 mg, 0.14 mmol) in dichloromethane (6 ml) was added diisopropylethylamine (0.070 ml, 0.4 mmol) followed by 4-methoxyphenylacetyl chloride (0.055 ml, 0.35 mmol). The reaction mixture was stirred at room temperature. After 18 h, water (2 ml) was added. The mixture was stirred for another 2 h. The mixture was sequentially washed with HCl (0.2 N, 2×15 ml), NaOH (0.2 N, 2×15 ml), and water (10 ml), dried (Na2SO4), filtered and concentrated to give N-((3-bromophenyl)methyl)-N-(1-(tert-butyloxycarbonyl)piperidin-4-yl)-4-methoxyphenylacetamide. The crude product was used without any further purification. N-((3-Bromophenyl)methyl)-N-(1-(tert-butyloxycarbonyl)piperidin-4-yl)-4-methoxyphenylacetamide was dissolved in diethyl ether (2 ml) and HCl (1 ml, 4 M in dioxane) was added. The reaction mixture was stirred at room temperature. After 2.5 h, NaOH (1 ml, 6 N) was added followed by dichloromethane (10 ml). The mixture was extracted with water (2×15 ml), dried (Na2SO4), filtered to give a clear solution. The solution was added on to a column carrying strongly acidic cation exchange resin (0.3 mmol/g resin), which was washed with methanol (3×6 ml), and eluted with 10% NH3 in methanol, and concentrated to give the title compound. Yield: 49 mg; 13C-NMR (CD3OD, rotamers): δ 26.6, 28.2, 40.2, 43.9, 44.0, 51.8, 54.1, 54.6, 113.76, 113.84, 114.1, 114.2, 122.2, 125.0, 125.5, 126.7, 127.1, 129.2, 129.5, 129.7, 129.8, 129.9, 130.0, 130.5, 130.6, 140.8, 141.8, 159.1, 173.3, 173.7.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[S:12][C:11]([C:13](O)=[O:14])=[CH:10][C:9]=2[C:16]2[CH:21]=[CH:20][C:19]([S:22]([CH3:25])(=[O:24])=[O:23])=[CH:18][CH:17]=2)=[CH:4][CH:3]=1.C(N1C=CN=C1)(N1C=CN=C1)=O.[NH2:38][C:39]1[NH:43][N:42]=[N:41][N:40]=1.Cl>O1CCCC1.O>[NH:40]1[C:39]([NH:38][C:13]([C:11]2[S:12][C:8]([C:5]3[CH:6]=[CH:7][C:2]([F:1])=[CH:3][CH:4]=3)=[C:9]([C:16]3[CH:21]=[CH:20][C:19]([S:22]([CH3:25])(=[O:24])=[O:23])=[CH:18][CH:17]=3)[CH:10]=2)=[O:14])=[N:43][N:42]=[N:41]1
Reactant: Nc1nnn[nH]1
Reactant: CS(=O)(=O)c1ccc(-c2cc(C(=O)O)sc2-c2ccc(F)cc2)cc1
Agent: Cl
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: O
Solvent: C1CCOC1
Product: CS(=O)(=O)c1ccc(-c2cc(C(=O)Nc3nnn[nH]3)sc2-c2ccc(F)cc2)cc1
Yield: 78.9 %

Procedure:
A mixture of 5-(4-fluorophenyl)-4-[4-(methylsulfonyl)phenyl]thiophene-2-carboxylic acid (1.0 g) and 1,1'-carbonyldiimidazole (0.45 g) in tetrahydrofuran (15 ml) was refluxed for 1.5 hours. 5-Aminotetrazole (0.226 g) was added and the mixture was refluxed for 3 hours. The mixture was diluted with water (50 ml), acidified with hydrochloric acid, and cooled in an ice-water bath. The precipitates were collected and recrystallized from ethanol to give colorless crystals of N-(5-tetrazolyl)-5-(4-fluorophenyl)-4-[4-(methylsulfonyl)phenyl]thiophene-2-carboxamide (0.93 g).
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][CH:4]([NH:7][C:8]([C:10]2[NH:11][C:12]3[C:17]([CH:18]=2)=[C:16]([O:19][CH2:20][CH:21]2[CH2:24][CH2:23][CH2:22]2)[CH:15]=[CH:14][CH:13]=3)=[O:9])[CH2:3][CH2:2]1.[C@H:25]1([CH2:35]O)[C@@H:34]2[N:29]([CH2:30][CH2:31][CH2:32][CH2:33]2)[CH2:28][CH2:27][CH2:26]1>>[C@H:25]1([CH2:35][N:1]2[CH2:6][CH2:5][CH:4]([NH:7][C:8]([C:10]3[NH:11][C:12]4[C:17]([CH:18]=3)=[C:16]([O:19][CH2:20][CH:21]3[CH2:24][CH2:23][CH2:22]3)[CH:15]=[CH:14][CH:13]=4)=[O:9])[CH2:3][CH2:2]2)[C@@H:34]2[N:29]([CH2:30][CH2:31][CH2:32][CH2:33]2)[CH2:28][CH2:27][CH2:26]1
Reactant: O=C(NC1CCNCC1)c1cc2c(OCC3CCC3)cccc2[nH]1
Reactant: OC[C@@H]1CCCN2CCCC[C@H]12
Product: O=C(NC1CCN(C[C@@H]2CCCN3CCCC[C@H]23)CC1)c1cc2c(OCC3CCC3)cccc2[nH]1

Procedure:
This compound is synthesized from 4-cyclobutylmethoxy-1H-indole-2-carboxylic acid piperidin-4-ylamide, 162 (preparation see below) and (1R,9aR)-1-(octahydro-quinolizin-1-yl)-methanol analogously to the method described in example 127.
Reaction SMILES: Cl.[NH:2]1[CH2:6][CH2:5][C@@H:4]([OH:7])[CH2:3]1.C(N(CC)CC)C.[CH2:15](Cl)[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1>ClCCl.C(Cl)(Cl)Cl.[OH-].[Na+]>[CH2:15]([N:2]1[CH2:6][CH2:5][C@@H:4]([OH:7])[CH2:3]1)[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1
Reactant: ClCc1ccccc1
Reactant: O[C@@H]1CCNC1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: ClCCl
Solvent: CCN(CC)CC
Solvent: ClC(Cl)Cl
Product: O[C@@H]1CCN(Cc2ccccc2)C1
Reaction time: 0.08 h
Yield: 44.4 %

Procedure:
The compound (3R)-pyrrolidin-3-ol hydrochloride (2.2 g, 17.8 mM) was dissolved in dichloromethane (25.0 ml) and triethylamine (5.0 ml, 35.6 mM) was added at room temperature with constant stirring for 5 minutes. Benzyl chloride (2.5 ml, 21.4 mM) was added to it in one lot at the same temperature followed by refluxing for 15 hours. The reaction mixture was diluted with chloroform and 1N sodium hydroxide (15.0 ml) was added with constant stirring for 10 minutes. The organic layer was separated and washed with aqueous sodium bicarbonate and brine solution. It was further dried over anhydrous sodium sulphate and concentrated to get the title compound. Yield=44.4% (1.4 g, 7.9 mM).
Reaction SMILES: [Cl:1][CH2:2][C:3]1[CH:8]=[CH:7][C:6]([CH2:9][CH2:10][C:11](Cl)=[O:12])=[CH:5][CH:4]=1.Cl.[CH3:15][O:16][C:17](=[O:27])[C@H:18]([CH2:20][C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1)[NH2:19].C(N(CC)CC)C.CCOC(C)=O>ClCCl>[Cl:1][CH2:2][C:3]1[CH:8]=[CH:7][C:6]([CH2:9][CH2:10][C:11]([NH:19][C@H:18]([C:17]([O:16][CH3:15])=[O:27])[CH2:20][C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)=[O:12])=[CH:5][CH:4]=1
Reactant: COC(=O)[C@@H](N)Cc1ccccc1
Reactant: O=C(Cl)CCc1ccc(CCl)cc1
Agent: Cl
Solvent: CCN(CC)CC
Solvent: CCOC(C)=O
Solvent: ClCCl
Product: COC(=O)[C@H](Cc1ccccc1)NC(=O)CCc1ccc(CCl)cc1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 35.9 %

Procedure:
To a cooled (0° C.), stirred solution of 1.6 g (6.2 mmol) of 3-[4-(chloromethyl)phenyl]propionyl chloride and 1.3 g (6.2 mmol) of phenylalanine methyl ester hydrochloride salt in 6 ml of dichloromethane was added 1.4 g (14 mmol) of triethylamine. The reaction mixture was stirred at 0° C. for 0.5 hour, poured into EtOAc and washed with water. The EtOAc layer was dried over Na2SO4, filtered and evaporated to afford an oil. This oil was flash chromatographed (40% EtOAc/hexanes) to give 0.8 g of product; m.p. 89°-90° C.
Reaction SMILES: [ClH:1].C(OC(=O)[NH:8][CH2:9][CH:10]1[CH2:15][CH2:14][N:13]([C:16]2[CH:25]=[C:24]3[C:19]([CH:20]=[CH:21][CH:22]=[N:23]3)=[CH:18][C:17]=2[NH:26][C:27]([C:29]2[CH:30]=[N:31][N:32]3[CH:37]=[C:36]([OH:38])[CH:35]=[N:34][C:33]=23)=[O:28])[CH2:12][CH2:11]1)(C)(C)C>ClCCl.N1C=CC=CC=1.O>[ClH:1].[NH2:8][CH2:9][CH:10]1[CH2:11][CH2:12][N:13]([C:16]2[CH:25]=[C:24]3[C:19]([CH:20]=[CH:21][CH:22]=[N:23]3)=[CH:18][C:17]=2[NH:26][C:27]([C:29]2[CH:30]=[N:31][N:32]3[CH:37]=[C:36]([OH:38])[CH:35]=[N:34][C:33]=23)=[O:28])[CH2:14][CH2:15]1
Reactant: CC(C)(C)OC(=O)NCC1CCN(c2cc3ncccc3cc2NC(=O)c2cnn3cc(O)cnc23)CC1
Agent: Cl
Solvent: O
Solvent: c1ccncc1
Solvent: ClCCl
Product: NCC1CCN(c2cc3ncccc3cc2NC(=O)c2cnn3cc(O)cnc23)CC1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A solution of hydrochloric acid (1 M in Et2O, 5 mL) was added to a solution of (1-{6-[(6-hydroxy-pyrazolo[1,5-a]pyrimidine-3-carbonyl)-amino]-quinolin-7-yl}-piperidin-4-ylmethyl)-carbamic acid tert-butyl ester (0.22 g) in a mixture of dichloromethane and methanol (1/1, 10 mL) and the resulting mixture was stirred at room temperature overnight. The solid formed was collected by filtration, washed with ethanol and dried under reduced pressure to give 224 mg of 6-hydroxy-pyrazolo[1,5-a]pyrimidine-3-carboxylic acid [7-(4-aminomethyl-piperidin-1-yl)-quinolin-6-yl]-amide hydrochloride as a light yellow powder. MS=418 [M+H]+; MP>300° C.